Fever is one of the most common conditions requiring an individual to seek medical attention. In addition to treating the cause of the fever, medical personnel treat, i.e., reduce, the fever itself using analgesics, antipyretics, and/or physical cooling methods.
The nonopioid analgesic and antipyretic drugs are a small, heterogeneous group of compounds which, unlike opioid analgesics, are free of significant addiction liability. Most of these nonopioid analgesic/antipyretic drugs affect both pain and fever. Consequently, they are widely used for minor aches and pains, headaches, and the general feeling of malaise that accompanies febrile illnesses, and to alleviate symptoms of rheumatic fever, arthritis, gout, and other musculoskeletal diseases and conditions.
The salicylate group of analgesics and antipyretics are by far the most commonly used. This group of drugs is consumed at a rate of more than 10,000 tons annually. In addition, paracetamol (i.e., acetaminophen) is one of the most widely used of all drugs, with a wealth of experience clearly establishing it as the standard antipyretic and analgesic for mild to moderate pain states. First used clinically by von Mering in 1893, acetaminophen was not used commercially in the United States until 1950. During the 1960s and 1970s, investigators voiced concerns about the toxicity of nonprescription analgesics, but in normal use, acetaminophen exhibited a consistent safety profile. Currently, acetaminophen is a first-line choice for pain management and antipyresis in a variety of patients, especially patients susceptible to the adverse effects of salicylates, including children, pregnant women, the elderly, individuals with osteoarthritis, and individuals with noninflammatory musculoskeletal conditions. See L. F. Prescott, Am. J. Ther., 7(2), pp. 143-147 (2000).
Acetaminophen is metabolized primarily in the liver, and the metabolites generally exhibit no harmful effects. The mechanism of action of acetaminophen has not been satisfactorily explained. Acetaminophen inhibits both COX-1 and COX-2 weakly in vitro, and reduces prostaglandin synthesis markedly in vivo. Evidence is accumulating for the existence of a COX-2 variant or a new COX enzyme that can be inhibited by acetaminophen (R. Botting, J. Physiol, Pharmacol., 54 (4 Pt. 1), pp. 609-698 (2000)). COX-2-selective drugs, or null mutation of the COX-2 gene, reduce or prevent fever. Acetaminophen is an antipyretic and analgesic, but it lacks the antiinflammatory and anticoagulatory properties of other nonsteroidal antiinflammatory drugs (NSAIDs). This has led to a theory that a COX variant capable of inhibition by acetaminophen exists. Inhibition of pharmacologically distinct COX-2 enzyme activity by acetaminophen, therefore, has been theorized as the mechanism of action of this important antipyretic drug (D. L. Simmons et al., Clin. Infect. Dis., 31 Supp. 5, pp. 5211-5218 (2000)).
The present invention is directed to the discovery that the antipyretic action of a nonopioid analgesic can be modified by coadministration of an endothelin receptor antagonist, hereafter termed an “endothelin antagonist.”